CASE REPORT published: 28 May 2019 doi: 10.3389/fped.2019.00210

Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With , Limb Reductions, and ESCO2 Mutations

Elisa Adele Colombo 1*, Hatice Mutlu-Albayrak 2, Yousef Shafeghati 3, Mine Balasar 4, Juliette Piard 5, Davide Gentilini 6,7, Anna Maria Di Blasio 6, Cristina Gervasini 1, Lionel Van Maldergem 5 and Lidia Larizza 8

1 Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy, 2 Department of Pediatric Genetics, Cengiz Gökcek Maternity and Children’s Hospital, Gaziantep, Turkey, 3 Sarem Cell Research Center and Medical Genetics Department, Sarem Women Hospital, Tehran, Iran, 4 Department of Medical Genetics, Meram Medical Edited by: Faculty, Necmettin Erbakan University, Konya, Turkey, 5 Centre de génétique humaine CHU, Université de Franche-Comté, Nagwa Elsayed Afify Gaboon, Besançon, France, 6 Laboratorio di Biologia Molecolare, Istituto Auxologico Italiano, IRCCS, Milan, Italy, 7 Department of Brain Ain Shams University, Egypt and Behavioral Sciences, University of Pavia, Pavia, Italy, 8 Laboratorio di Citogenetica e Genetica Molecolare Umana, Istituto Reviewed by: Auxologico Italiano, IRCCS, Milan, Italy Alistair Duncan Calder, Great Ormond Street Hospital, United Kingdom Baller-Gerold (BGS, MIM#218600) and Roberts (RBS, MIM#268300) syndromes are Nermine Salah Eldine Elsayed, rare autosomal recessive disorders caused, respectively, by biallelic alterations in Ain Shams University, Egypt RECQL4 (MIM∗603780) and ESCO2 (MIM∗609353) genes. Common features are severe *Correspondence: Elisa Adele Colombo growth retardation, limbs shortening and craniofacial abnormalities which may include [email protected] craniosynostosis. We aimed at unveiling the genetic lesions underpinning the phenotype of two unrelated children with a presumptive BGS diagnosis: patient 1 is a Turkish girl with Specialty section: This article was submitted to short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface Genetic Disorders, hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus. a section of the journal Patient 2 is an Iranian girl born to consanguineous parents with craniosynostosis, Frontiers in Pediatrics , bilateral radial aplasia, thumbs, and in the context of Received: 22 November 2018 Accepted: 08 May 2019 developmental delay. Upon negative RECQL4 test, whole exome sequencing (WES) Published: 28 May 2019 analysis performed on the two trios led to the identification of two different ESCO2 Citation: homozygous inactivating variants: a previously described c.1131+1G>A transition in Colombo EA, Mutlu-Albayrak H, Shafeghati Y, Balasar M, Piard J, patient 1 and an unreported deletion, c.417del, in patient 2, thus turning the diagnosis Gentilini D, Di Blasio AM, Gervasini C, into Roberts syndrome. The occurrence of a Baller-Gerold phenotype in two unrelated Van Maldergem L and Larizza L (2019) patients that were ultimately diagnosed with RBS demonstrates the strength of WES Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two in redefining the nosological landscape of rare congenital malformation syndromes, Patients With Craniosynostosis, Limb a premise to yield optimized patients management and family counseling. Reductions, and ESCO2 Mutations. Front. Pediatr. 7:210. Keywords: Roberts syndrome, Baller-Gerold syndrome, RECQL4, ESCO2, patient management, genetic doi: 10.3389/fped.2019.00210 counseling, differential diagnosis

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BACKGROUND Biallelic pathogenic variants in ESCO2 (establishment of cohesion 1 homolog 2; OMIM∗609353) gene located at 8p21.1, Baller-Gerold syndrome (BGS, OMIM#218600) (1) and have been identified in RBS and SC Phocomelia (2). ESCO2 Roberts syndrome (RBS, OMIM#268300) (2) are two rare encodes an acetyltransferase of the cohesion establishing autosomal recessive congenital disorders with clinical overlap complex involved in sister chromatids cohesion during DNA and a broad phenotypic variability. replication and double-strand breaks repair (16). No genotype- The major clinical findings of BGS involve the skeleton: all phenotype correlation has been established so far. A variable patients display craniosynostosis of any or all cranial sutures clinical presentation between sibs, including both RBS and and pre-axial upper limb defects, mainly hypoplasia/aplasia SC Phocomelia phenotypes, suggests that modifier genes and of radii, ulnae, and/or thumbs and malformation or absence epigenetic factors contribute to this uncommon variability of some carpal and metacarpal bones. The spectrum of BGS among autosomal recessive disorders (2). Mildly affected manifestations includes also growth delay, anomalies of lower children are probably overrepresented in the published clinical limbs (absent patellae, , club feet), imperforate or descriptions since they are more likely to survive and to come to anteriorly placed anus, rectovaginal fistula, renal and cardiac medical attention. (tetralogy of Fallot, ventricular septal defects) malformations, We herein report on two unrelated cases of RBS who were skin alterations (poikiloderma, hyper- and hypopigmentation, first clinically diagnosed as BGS and, upon negative RECQL4 hemangioma, nevus flammeus), facial dysmorphisms test, were found by whole exome sequencing (WES) to harbor (telecanthus, malpositioned ears, prominent/depressed nasal homozygous mutations in ESCO2 gene. One of the observed bridge, high-arched/cleft palate, micrognathia), and occasionally variants, yet unreported, expands ESCO2 mutational spectrum. intellectual disability. Many BGS patients die within the first year of life and a few may develop malignancies early in life (3, 4). CASE PRESENTATION About 70 clinically diagnosed BGS patients are reported in the literature but, subsequently to further in-depth analysis, We describe two affected patients of two unrelated families a different diagnosis has been formulated for almost 20 of (1 and 2) with a syndromic phenotype suggestive of BGS them (3, 5–9). To date, biallelic alterations in RECQL4 gene referred to our laboratory by clinical geneticists and pediatricians. ∗ (OMIM 603780), encoding a protein of the RECQ helicase Appropriate written informed consent to genetic analysis and family with multiple functions in the maintenance of genome authorization to photos collection were obtained from the integrity, have been found in a subgroup of 11 BGS patients parents of the patients for the publication of the case report from 7 families (1, 4, 10–12). To note, 4 out of 5 BGS patients, and any potentially-identifying information/images. The study who could be evaluated, present with poikiloderma, a chronic protocol was approved by the Research Ethics Board of Istituto cutaneous alteration manifesting in the first years of life in most Auxologico Italiano, Milan, Italy. of the RECQL4-mutated patients (4, 10, 11). Roberts syndrome, which includes SC Phocomelia syndrome Clinical Report of Family 1 (OMIM#269000), is a multiple malformation syndrome (2) Proband 1 is the second child of Turkish parents originating from described in at least 230 patients belonging to 167 different the same geographical area. She was born in 2005 at full-term families. Its main clinical features include severe pre- and after an uneventful pregnancy and presented with mesomelic post-natal growth retardation, symmetrical tetra-limb reduction shortening of limbs and bilateral thumb aplasia. She has an elder of various degree (usually more severe in upper limbs) associated brother who suffered from epilepsy, motor delay and intellectual to skeletal defects including absence or reduction in length of disability, and a 1-year-old sister who had an epileptic attack at8 humeri, radii and thumbs, ulna deformity, , and months of age (Figure 1A). neurological signs, such as mild to severe intellectual disability Early in infancy, bilateral corneal clouding was noted and and seizures. Craniofacial dysmorphisms (, cleft surgically removed. Due to eye proptosis and cranial deformity, lip, cleft palate, nose and ears anomalies), microcephaly, facial she underwent a skull radiograph and CT scan that indicated hemangioma, congenital heart defects, polycystic or dysplastic sagittal and coronal premature fusion. She manifested motor and kidneys, and enlarged genitalia are frequently observed in RBS developmental delay. Language was delayed and limited to a few patients. The most severe phenotypes usually lead to fetal death words without the ability to construct sentences. or in the first months of life. SC Phocomelia is considered Generalized seizures, responsive to levetiracetam, occurred the mild clinical variant of RBS (13) and is characterized when she was 8-year old; her height was at −8.5 SD (80cm), by mild symmetric limb reductions, joint contractures, weight at −4.8 SD (10kg), and OFC at −7 SD (43 cm). microcephaly, midfacial hemangioma, cloudy corneas, and On clinical examination at 12 years, she could not follow an mild or borderline intellectual disability. Survival to adulthood is object with her eyes nor speak or respond to questions. Facial common (14). dysmorphisms included low anterior and posterior hairlines, At the cellular level, the chromosomal instability hallmark arched eyebrows, telecanthus, epicanthal folds, eye proptosis, of premature centromere separation and splitting of the left exotropia, cutaneous hemangioma on the frontal region heterochromatic regions, also termed “heterochromatic expanding to the nose which is small and flared, a short philtrum, repulsion” (HR), characterize metaphase spreads of RBS-SC wide mouth with downturned corners and high-arched palate Phocomelia cells (15). (Figure 1B). Her upper limbs were extremely short, thumbs

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FIGURE 1 | Clinical and molecular features of patients 1 and 2. (A) Pedigree of family 1: the arrow indicates the proband. (B) Face of patient 1 at 12 years showing arched eyebrows, telecanthus, epicanthal folds, hemangioma on the frontal region, small and flared nose, short philtrum, and a wide mouth with downturned corners. (C) Forearm aplasia, manus , and thumb aplasia. (D) Close-up of the left leg showing short cruris, flexion deformity on , and pes equinovarus. (E) Overall photo of patient 1 showing dysmorphisms of the face and malformations of and legs. (F) Coronal cross-sectional areas obtained with cranial MR T2 showing asymmetric colpocephalic expansion of lateral ventricles occipital horns. (G,H) X-rays images of arms showing bilaterally aplasia of radius, ulna and thumb, (Continued)

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FIGURE 1 | hypoplasia of middle phalanx, fusion of 4–5 metacarpals and carpal bones. (I) Sagittal cross-sectional areas obtained with cranial MR T2 showing partial corpus callosum agenesis. (J,K) X-rays images of the legs evidencing bilaterally fibular aplasia, femoral-tibial , fusion of tarsal bones, short and bowed tibias. (L) Chromatograms of ESCO2 sequence around c.1131+1G>A in intron 6 of the affected girl (top) and her obligate carriers parents (middle and bottom). Fex6 ′ ′ ′ ′ (5 -gaggaccaggatttgagtgtt-3 ) and Rex6 (5 -accacctacaactcccattct-3 ) primers were used to amplify this region. (M) C-banded metaphase spread showing premature centromere separation with puffing at the centromere and heterochromatic regions (arrowed). (N) Pedigree of family 2 with RBS-affected patient arrowed. (O) Photograph of patient 2, showing forearm aplasia, varus deformity of hands, thumb aplasia, extended capillary malformation, and sparse hair. Magnifications showing the protruding cupped ear (P) and the short nose with underdeveloped alae nasi and narrow and sharp nasal ridge (Q). (R) Coronal craniosynostosis and profile view of head X-rays. (S) Chromatograms of ESCO2 sequence around c.417del alteration in exon 3 in the affected girl (top) and her obligate ′ ′ ′ ′ carriers parents. The exon 3-specific amplicons were obtained using primers Fex3 (5 -gcaaatcaaggctcacca-3 ) and Rex3 (5 -ttttggctcagaacccga-3 ). absent while fingers were long and tibias short and bowed their functional impact (i.e., non-sense, affecting the canonical (Figures 1C,E). There was an equinovarus deformity of the right splice-site regions or non-synonymous) and the prediction of foot and calcaneus on the left foot, overriding Polyphen (23) and SIFT (24) bioinformatics tools. toes and major joints contractures (Figures 1D,E). The skeletal Filtering about 43,500 variants in each sample led to survey showed bilateral aplasia of radius, ulna, and thumb the identification of two different ESCO2 (NG_008117.1) (Figures 1G,H,J,K) while brain MRI evidenced asymmetric homozygous alterations in the probands: c.1131+1G>A in dilatation of lateral ventricles and agenesis of corpus callosum intron 6 of patient 1 and c.417del in exon 3 of patient 2 [sequence (Figures 1F,I). Karyotype was 46,XX on peripheral lymphocytes. variants were termed according to HGVS recommendations Array-CGH was normal. (25)]. Sanger sequencing confirmed the biallelic pathogenic alterations in the probands and the carrier status of their parents Clinical Report of Family 2 (Figures 1L,S) and of the elder brother of patient 1. The splice Proband 2 is a 2-year-old Iranian girl born to consanguineous donor variant c.1131+1G>A has a MAF < 0.01 and has been parents, presenting with a malformation syndrome comprising previously reported (13, 26–28) while the c.417del is absent from craniosynostosis, bilateral radial ray hypoplasia and absent public databases, has not been described to date and has been thumbs (Figures 1N,O,R). The pregnancy was unremarkable submitted to LOVD database (https://databases.lovd.nl/shared/ till 6 months of gestation when ultrasonographic examination genes/ESCO2). revealed oligohydramnios and bilateral club feet. The baby The final diagnosis of Roberts syndrome was done in was born at 29 weeks of gestation and her birth weight both cases. Moreover, C-banding chromosome analysis of was 720 g. A large frontal hemangioma and craniofacial patient 1 showed the premature centromere separation and dysmorphisms including large alae nasi, small nose with deep heterochromatin repulsion known to be pathognomonic for nasal bridge, arched palate, micrognathia, simple ears, and RBS (Figure 1M). short neck were observed since birth (Figures 1O–Q). She had bilateral hypoplastic radius, oligodactyly, and joints stiffness. Bilateral glaucoma and hypotonia were also noted. DISCUSSION Neurodevelopmental delay and hypothyroidism were recorded. To better compare the characteristics of our patients with those of the RBS-SC Phocomelia patients reported in the literature LABORATORY INVESTIGATIONS with the same recurrent mutation of case 1 or with a different mutation but affecting the same nucleotide of case 2, we provide A provisional clinical diagnosis of Baller-Gerold syndrome an overview of all known ESCO2 pathogenic variants. As can was made for both patients based on the association of be seen at glance in Figure 2 there is no hot spot as the craniosynostosis and radial ray defects. However, RECQL4 mutations are scattered throughout the gene. To date, out of Sanger sequencing carried on as previously described (17) didn’t 33 different pathogenic variants described in 49 families, 31 are evidence any significant sequence alteration. inactivating mutations leading to protein truncation and lack For both families, WES was performed on 50 ng of genomic of the evolutionarily conserved C-terminal domain where the DNA of each member of the trio (index patient and parents) acetyltransferase activity is harbored. prepared using the IlluminaR NexteraR Rapid Capture Exome The c.1131+1G>A alteration of family 1 has been previously kit (Illumina) and sequenced on Illumina HiSeq2500 sequencer reported in literature both in homozygous (13, 26, 27) and (Illumina). Reads were aligned against the human reference compound heterozygous (28) state and it has been demonstrated genome (hg 19/GRCh37) using the Burrows-Wheeler Alignment that the mutated allele codifies for an aberrant transcript lacking tool (18). The variant calling was performed with the SAM tool exon 6 (r.1014_1131del118) and exposing a premature stop (19) and the variant annotation with GATK (20). codon (p.Arg338fs∗17) (13). The clinical phenotype of the three Given the rarity of the suspected disease, the variant list was patients with the c.1131+1G>A homozygous splicing mutation filtered according to an allele frequency ≤0.1% according to is, although variable, ranging from the mildest phenotype of the ExAC Browser of Broad Institute (21) and 1,000 Genomes the adult patient with SC Phocomelia syndrome (13) to the (22) databases. Subsequent filtering steps sorted out variants most severe of RBS in an infant prematurely died (27). All following the autosomal recessive inheritance model as well as patients share dysmorphisms, microcephaly, and skeletal defects.

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FIGURE 2 | ESCO2 pathogenic alterations. Schematic diagram of full-length ESCO2 gene: exons are depicted as boxes while introns as thin bars. Exons encoding the acetyltransferase domain are in dark gray. The two mutations carried by the patients herein described are over the gene schematic while all the 32 known pathogenic alterations found in RBS-SC Phocomelia patients are listed below. The only 3 “non-inactivating” mutations (2 missense mutations and a three-nucleotide deletion) are bolded. The horizontal dashed lines indicate intronic mutations leading to miss-splicing.

Compound heterozygosity for this splice site alteration and the TABLE 1 | Summary of the major clinical signs of BGS and RBS according to the c.954_955+2del sequence alteration was also described in a clinically and molecularly investigated patients with either syndrome. female RBS fetus with multiple malformations (limbs alterations, BGS RBS hygroma, and intrauterine growth retardation) deceased at 18 RECQL4+ ESCO2+ weeks of gestation (28). At difference from our patient, none of the described patients was reported to suffer from epilepsy N◦ of patients (n◦ offetuses) 11(5) 61(13) as well as craniosynostosis, which are rarely described in RBS Pre/post-natal growth delay 4 52 patients (13, 15, 29, 30). However, one may suppose that epilepsy Craniosynostosis 9 4 in our RBS patient may represent a comorbid condition due to Craniofacial dysmorphisms 4 38 segregation of a common recessive epilepsy gene from the likely Hemangioma 1 30 related parents, given that also proband’s siblings suffer from Upper limbs malformations 11 61 seizures but do not have RBS. Lower limbs malformations 7 61 As regards the single nucleotide c.417del deletion (Figure 2) Intellectual disability/developmental delay 1 23 identified in patient 2, it has not been reported in the literature so far. It is worth noting that a duplication involving the same nucleotide has been observed (31) in a Turkish fetus with In addition, cognitive impairment is more severe in RBS than RBS (29). BGS: most RBS patients show not only developmental delay but Our RBS patients masqueraded as Baller-Gerold syndrome also a severe intellectual disability even if marked variability exists patients due to craniosynostosis, uncommon in RBS, and radial between RBS and SC Phocomelia (2). ray hypoplasia, a major BGS sign which in RBS presents in Moreover, 90% (10/11) BGS (10–12, 32, 33, 36) and all the general context of upper limb reductions. In addition, both RBS (14, 27–29, 34, 35, 37, 38) patients present with radial patients had a severe developmental delay, midface hemangioma, alterations (hypo/aplasia) and most of them manifest additional striking facial dysmorphism more severe than that usually upper and lower limb malformations. Pre-axial upper limb observed in coronal or sagittal craniosynostosis. Overall, these defects are similar in BGS and RBS: ulnae hypoplasia, club clinical signs and symptoms encompass and surpass the classical hands, thumbs aplasia/hypoplasia, , and oligodactyly, Baller-Gerold clinical picture. though humeral reduction can be also present in RBS. Table 1 summarizes the distinctive clinical features of Conversely, marked differences in lower limb malformations BGS and RBS individuals whose clinical phenotype could be exist between BGS and RBS (Table 1): and knee joint confirmed by molecular analysis of the respective RECQL4 and dislocation, patellar aplasia, or hypoplasia, hypoplasia of great ESCO2 genes. Craniosynostosis is a distinctive sign of BGS as it toe, club feet have been reported in BGS while in RBS lower has been reported in 82% (9/11) of BGS patients with RECQL4 limb malformations include femoral, tibial and fibular hypoplasia alterations (4, 10–12, 32, 33) but in RBS with ESCO2 pathogenic or aplasia, club feet, and knee joint dislocation. As known, RBS variants only in the 2 patients herein described and in 2 patients malformations of upper limbs are more severe than those of of the literature, for whom no details or images are provided (29). lower limbs, and some patients present skeletal defects only in Conversely, hemangioma on the face, recorded in 30 ESCO2+ the arms (2). patients (29, 34, 35) and in only one RECQL4+ patient (10, 32), Several additional anomalies have been observed in BGS as well as intellectual disability, assessed in 23 ESCO2+ patients and RBS patients with a severe phenotype, who can present (29, 34) and in 1 RECQL4+ patient (4), are prominent in RBS. multiple additional abnormalities coupling only with one

Frontiers in Pediatrics | www.frontiersin.org 5 May 2019 | Volume 7 | Article 210 Colombo et al. From Baller-Gerold to Roberts Syndrome syndrome. Poikiloderma (4, 10, 11, 33), imperforate and/or However, the diagnosis of ultra-rare syndromes characterized anteriorly positioned anus (4, 10, 32), feeding difficulties (10, by a huge clinical spectrum, such as BGS and RBS, is quite 11, 33), hypospadias and undescended testes (33), and osseous challenging and benefits enormously from the application of demineralization (11, 33) have been recorded only in BGS contemporary molecular genomics techniques allowing the patients, while heart defects (14, 27, 29, 34, 35, 38) and unequivocal identification of the genetic lesion behind the enlargement of phallus/clitoris (29) have been reported only in disease. The suspected diagnosis can be confirmed/excluded, RBS. Before the availability of the molecular test, heart defects hence enhancing optimized patient management/follow-up, as well as seizure, have been included in the spectrum of BGS family counseling and appropriate therapy provision. signs (39) but none of BGS patients with RECQL4 alterations manifested these clinical findings, a data raising the possibility ETHICS STATEMENT that many patients described in the past had received the wrong diagnosis of BGS, as it has been confirmed in a few cases (7–9). The study protocol was approved by the Research Ethics Board The clinical overlap of BGS, a RECQL4-associated disease, of Istituto Auxologico Italiano, Milano, Italy. and RBS cohesinopathy is accounted for by the interconnected For each patient, appropriate written informed consent to pathways of the respective genes, as evidenced by the inclusion genetic analysis and authorization to photos collection and of RECQL4 among the accessory proteins acting in the cohesin publication were obtained by parents. pathway (40) and by downregulation of RECQL4 in Cornelia de Lange (OMIM#122470) patients (41). Both RECQL4 and AUTHOR CONTRIBUTIONS ESCO2 contribute to the maintenance of correct chromosomal segregation and syndrome-specific hallmarks of chromosomal EAC carried out the genetic analyses and analyzed WES instability are observed when both alleles of these key genes are variants, drafted the manuscript. HMA examined patient 1 and deranged (42, 43). summarized clinical data and critically reviewed the manuscript. Switching back to BGS-RBS phenotypic similarity one has YS examined patient 2 and summarized clinical data. MB to note that this analysis suffers from the limited number of examined patient 1, summarized clinical data, and performed survived and clinically evaluated BGS individuals (out of 11 cases cytogenetic analysis. JP examined patients 2 and summarized there are five terminated pregnancies (10, 11, 36) and one death clinical data. DG performed next-generation sequencing. AMDB occurred few minutes after birth (10, 32) vs. the much higher supported WES analyses. CG supported genetic and variants number of RBS patients (29 patients >1 year) (14, 29, 34). Such filtering analyses and reviewed the manuscript. LV examined disproportion makes hard to compare the frequency of especially patients, summarized clinical data, and critically reviewed rare clinical findings, such as craniosynostosis, between RBS and the manuscript. LL conceptualized and designed the study, BGS patients. A further difficulty arises from the wide clinical coordinated the work, drafted and reviewed the manuscript. All expressivity of both syndromes, deserving a consistent number authors read and approved the final manuscript. of described patients, not yet available for BGS, to classify signs recorded only in one or few patients. FUNDING CONCLUDING REMARKS This work was supported by Italian Ministry of Health to Istituto Auxologico Italiano (Ricerca Corrente 08C624 to LL). The similarity in upper limb malformations and pre/post-natal growth delay in BGS and RBS joined to the peculiarity of ACKNOWLEDGMENTS additional syndrome-specific malformations, can help clinicians in the clinical diagnosis. We thank the family members for their cooperation.

REFERENCES 4. Debeljak M, Zver A, Jazbec J. A patient with Baller-Gerold syndrome and midline NK/T lymphoma. Am J Med Genet A. (2009) 149A:755– 1. Van Maldergem L. Baller-Gerold Syndrome. In: Adam MP, Ardinger HH, 9. doi: 10.1002/ajmg.a.32736 Pagon RA, Wallace SE, Bean LJ, Stephens K, et al. editors. GeneReviewsR 5. Farrell SA, Paes BA, Lewis ME. Fanconi anemia in a child previously Seattle, WA: University of Washington (1993). Available online at: http:// diagnosed as Baller-Gerold syndrome. Am J Med Genet. (1994) 50:98– www.ncbi.nlm.nih.gov/books/NBK1204/. (accessed April 15, 2019). 9. doi: 10.1002/ajmg.1320500123 2. Gordillo M, Vega H, Jabs EW. Roberts Syndrome. In: Adam MP, Ardinger 6. Rossbach HC, Sutcliffe MJ, Haag MM, Grana NH, Rossi AR, HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al. editors. GeneReviewsR Barbosa JL. Fanconi anemia in brothers initially diagnosed with Seattle, WA: University of Washington (1993). Available online at: http:// VACTERL association with , and subsequently www.ncbi.nlm.nih.gov/books/NBK1153/. (accessed April 15, 2019). with Baller-Gerold syndrome. Am J Med Genet. (1996) 61:65–7. 3. Preis S, Majewski F, Körholz D, Göbel U. Osteosarcoma doi: 10.1002/(SICI)1096-8628(19960102)61:1<65::AID-AJMG12>3.0.CO;2-U in a 16-year-old boy with Baller-Gerold syndrome. Clin 7. Gripp KW, Stolle CA, Celle L, McDonald-McGinn DM, Whitaker Dysmorphol. (1995) 4:161–8. doi: 10.1097/00019605-199504000- LA, Zackai EH. TWIST gene mutation in a patient with radial 00009 aplasia and craniosynostosis: further evidence for heterogeneity

Frontiers in Pediatrics | www.frontiersin.org 6 May 2019 | Volume 7 | Article 210 Colombo et al. From Baller-Gerold to Roberts Syndrome

of Baller-Gerold syndrome. Am J Med Genet. (1999) 82:170–6. 28. Dupont C, Bucourt M, Guimiot F, Kraoua L, Smiljkovski D, Le doi: 10.1002/(SICI)1096-8628(19990115)82:2<170::AID-AJMG14>3.0.CO;2-X Tessier D, et al. 3D-FISH analysis reveals chromatid cohesion defect 8. Seto ML, Lee SJ, Sze RW, Cunningham ML. Another TWIST on Baller-Gerold during interphase in Roberts syndrome. Mol Cytogenet. (2014) syndrome. Am J Med Genet. (2001) 104:323–30. doi: 10.1002/ajmg.10065 7:59. doi: 10.1186/s13039-014-0059-6 9. Piard J, Aral B, Vabres P, Holder-Espinasse M, Mégarbané A, Gauthier S, 29. Vega H, Trainer AH, Gordillo M, Crosier M, Kayserili H, Skovby F, et al. et al. Search for ReCQL4 mutations in 39 patients genotyped for suspected Phenotypic variability in 49 cases of ESCO2 mutations, including novel Rothmund-Thomson/Baller-Gerold syndromes. Clin Genet. (2015) 87:244– missense and codon deletion in the acetyltransferase domain, correlates with 51. doi: 10.1111/cge.12361 ESCO2 expression and establishes the clinical criteria for Roberts syndrome. J 10. Van Maldergem L, Siitonen HA, Jalkh N, Chouery E, De Roy M, Delague V, Med Genet. (2010) 47:30–7. doi: 10.1136/jmg.2009.068395 et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller- 30. Eylon S, Beeri M, Joseph K, Meyer S. Femorotibial ankylosis in a child Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet. with Roberts syndrome: an ≪aggressive≫ approach to habilitation. J Pediatr (2006) 43:148–52. doi: 10.1136/jmg.2005.031781 Orthop. (2007) 27:926–9. doi: 10.1097/bpo.0b013e31815a6045 11. Siitonen HA, Sotkasiira J, Biervliet M, Benmansour A, Capri Y, Cormier-Daire 31. Vega H, Waisfisz Q, Gordillo M, Sakai N, Yanagihara I, Yamada M, et al. V,et al. The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. (2009) Roberts syndrome is caused by mutations in ESCO2, a human homolog of 17:151–8. doi: 10.1038/ejhg.2008.154 yeast ECO1 that is essential for the establishment of sister chromatid cohesion. 12. Kaneko H, Izumi R, Oda H, Ohara O, Sameshima K, Ohnishi H, et al. Nat Genet. (2005) 37:468–70. doi: 10.1038/ng1548 Nationwide survey of Baller-Gerold syndrome in Japanese population. Mol 32. Van Maldergem L, Verloes A, Lejeune L, Gillerot Y. The Baller-Gerold Med Rep. (2017) 15:3222–4. doi: 10.3892/mmr.2017.6408 syndrome. J Med Genet. (1992) 29:266–8. doi: 10.1136/jmg.29.4.266 13. Schüle B, Oviedo A, Johnston K, Pai S, Francke U. Inactivating mutations in 33. Mégarbané A, Melki I, Souraty N, Gerbaka J, El Ghouzzi V, Bonaventure J, ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype et al. Overlap between Baller-Gerold and Rothmund-Thomson syndrome. correlation. Am J Hum Genet. (2005) 77:1117–28. doi: 10.1086/498695 Clin Dysmorphol. (2000) 9:303–5. doi: 10.1097/00019605-200009040- 14. Goh ES-Y, Li C, Horsburgh S, Kasai Y, Kolomietz E, Morel CF. The 00018 Roberts syndrome/SC phocomelia spectrum–a case report of an adult 34. Afifi HH, Abdel-Salam GMH, Eid MM, Tosson AMS, Shousha WG, Abdel with review of the literature. Am J Med Genet A. (2010) 152A:472– Azeem AA, et al. Expanding the mutation and clinical spectrum of Roberts 8. doi: 10.1002/ajmg.a.33261 syndrome. Congenit Anom. (2016) 56:154–62. doi: 10.1111/cga.12151 15. Tomkins D, Hunter A, Roberts M. Cytogenetic findings in 35. Mengen E, Kotan LD, Ucakturk SA, Topaloglu AK, Yuksel B. A novel Roberts-SC phocomelia syndrome(s). Am J Med Genet. (1979) frameshift mutation in ESCO2 gene in roberts syndrome. J Coll Physicians 4:17–26. doi: 10.1002/ajmg.1320040104 Surg Pak. (2018) 28:403–5. doi: 10.29271/jcpsp.2018.05.403 16. Unal E, Heidinger-Pauli JM, Koshland D. DNA double-strand breaks trigger 36. Cao DH, Mu K, Liu DN, Sun JL, Bai XZ, Zhang N, et al. Identification of genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science. (2007) novel compound heterozygous RECQL4 mutations and prenatal diagnosis 317:245–8. doi: 10.1126/science.1140637 of Baller-Gerold syndrome: a case report. Genet Mol Res. (2015) 14:4757– 17. Colombo EA, Locatelli A, Cubells Sánchez L, Romeo S, Elcioglu NH, Maystadt 66. doi: 10.4238/2015.May.11.8 I, et al. Rothmund-Thomson Syndrome: insights from new patients on the 37. Gerkes EH, van der Kevie-Kersemaekers A-MF, Yakin M, Smeets DFCM, van genetic variability underpinning clinical presentation and cancer outcome. Int Ravenswaaij-Arts CMA. The importance of chromosome studies in Roberts J Mol Sci. (2018) 19:E1103. doi: 10.3390/ijms19041103 syndrome/SC phocomelia and other cohesinopathies. Eur J Med Genet. (2010) 18. Li H, Durbin R. Fast and accurate long-read alignment with 53:40–4. doi: 10.1016/j.ejmg.2009.10.005 Burrows-Wheeler transform. Bioinformatics. (2010) 26:589– 38. Socolov RV,Andreescu NI, Haliciu AM, Gorduza EV,Dumitrache F, Balan RA, 95. doi: 10.1093/bioinformatics/btp698 et al. Intrapartum diagnostic of Roberts syndrome - case presentation. Rom J 19. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. Morphol Embryol. (2015) 56:585–8. The sequence alignment/map format and SAMtools. Bioinformatics. (2009) 39. Temtamy SA, Aglan MS, Nemat A, Eid M. Expanding the phenotypic 25:2078–9. doi: 10.1093/bioinformatics/btp352 spectrum of the Baller-Gerold syndrome. Genet Couns. (2003) 14:299–312. 20. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. 40. Krantz ID. Cohesin embraces new phenotypes. Nat Genet. (2014) 46:1157– A framework for variation discovery and genotyping using next-generation 8. doi: 10.1038/ng.3123 DNA sequencing data. Nat Genet. (2011) 43:491–8. doi: 10.1038/ng.806 41. Liu J, Zhang Z, Bando M, Itoh T, Deardorff MA, Clark D, et al. Transcriptional 21. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. dysregulation in NIPBL and cohesin mutant human cells. PLoS Biol. (2009) Analysis of protein-coding genetic variation in 60,706 humans. Nature. (2016) 7:e1000119. doi: 10.1371/journal.pbio.1000119 536:285–91. doi: 10.1038/nature19057 42. Larizza L, Magnani I, Roversi G. Rothmund-Thomson syndrome and 22. The 1000 Genomes Project Consortium. A global reference for human genetic RECQL4 defect: splitting and lumping. Cancer Lett. (2006) 232:107– variation. Nature. (2015) 526:68–74. doi: 10.1038/nature15393 20. doi: 10.1016/j.canlet.2005.07.042 23. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, 43. Jabs EW, Tuck-Muller CM, Cusano R, Rattner JB. Studies of mitotic et al. A method and server for predicting damaging missense mutations. Nat and centromeric abnormalities in Roberts syndrome: implications for Methods. (2010) 7:248–9. doi: 10.1038/nmeth0410-248 a defect in the mitotic mechanism. Chromosoma. (1991) 100:251– 24. Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect 61. doi: 10.1007/BF00344159 protein function. Nucleic Acids Res. (2003) 31:3812–4. doi: 10.1093/nar/g kg509 Conflict of Interest Statement: The authors declare that the research was 25. den Dunnen TJ, Dalgleish R, Maglott DR, Hart RK, Greenblatt conducted in the absence of any commercial or financial relationships that could MS, McGowan-Jordan J, et al. HGVS Recommendations for the be construed as a potential conflict of interest. Description of Sequence Variants: 2016 Update. Hum Mutat. (2016) 37:564–9. doi: 10.1002/humu.22981 Copyright © 2019 Colombo, Mutlu-Albayrak, Shafeghati, Balasar, Piard, Gentilini, 26. Gordillo M, Vega H, Trainer AH, Hou F, Sakai N, Luque R, et al. Di Blasio, Gervasini, Van Maldergem and Larizza. This is an open-access article The molecular mechanism underlying Roberts syndrome involves loss distributed under the terms of the Creative Commons Attribution License (CC BY). of ESCO2 acetyltransferase activity. Hum Mol Genet. (2008) 17:2172– The use, distribution or reproduction in other forums is permitted, provided the 80. doi: 10.1093/hmg/ddn116 original author(s) and the copyright owner(s) are credited and that the original 27. Dogan M, Firinci F, Balci YI, Zeybek S, Ozgürler F, Erdogan I, et al. The publication in this journal is cited, in accordance with accepted academic practice. Roberts syndrome: a case report of an infant with valvular aortic stenosis and No use, distribution or reproduction is permitted which does not comply with these mutation in ESCO2. J Pak Med Assoc. (2014) 64:457–60. terms.

Frontiers in Pediatrics | www.frontiersin.org 7 May 2019 | Volume 7 | Article 210